Basal Ganglia & Cerebellum - a brief overview

The previous blog post talked about the "hierarchy" of the sensorimotor system, ranging from the highest order of the brain (cerebral cortex) down to the brainstem and the spinal cord. There are two more parts of the CNS that are essential in motor control and we'll discuss them here.

Fig-1: The position of the cerebral cortex, basal ganglia, brainstem, and cerebellum in the motor hierarchy with ways how they influence each other. Both the corticostriatal loop and the corticopontine-cerebellar go through the thalamus.

Outputs from the motor cortex are connected to several subcortical nuclei called the basal ganglia (BG) and the cerebellum. These two compartments are known to influence and modulate movement performance such as accuracy and timely execution. Basal ganglia are especially known to give Go/No-Go signal to the cortex. The role thalamus is particularly essential to convey the information back to the cerebral cortex from the corticostriatal and the corticopontine-cerebellar loop. To complete the topic, it is worthwhile to look at the left diagram.

What are Basal Ganglia?
They are essentially a group of subcortical motor nuclei that include:
(1) The striatum, comprising the caudate nucleus & putamen. They form input channels to BG.
(2) The globus pallidum structures: external (GPe) and internal (GPi) segments.
(3) Substantia nigra at the base of the midbrain.
(4) Subthalamic nucleus (STN), located below or ventral to the thalamus.

The striatum is located at the base of the forebrain lateral to the thalamus and is separated by the internal capsule into the caudate and putamen internally. The structure is 95% composed of a specific type of GABAergic neurons called the medium spiny neurons. Depending on the location, these neurons express different dopaminergic receptors (D1 or D2). Substantia nigra contains two distinct divisions. First, the more medial pars compacta (SNpc) contains dopaminergic neurons that send projections to the striatum. Second, the more lateral pars reticulata (SNpr) contains GABAergic neurons. Together with GPi, SNpr is considered the BG output channels.

Refer to the diagram shown in Fig-2. The concept of Go/No-Go comes from the fact that basal ganglia are able to enhance or inhibit a movement through the influence of two major pathways: the direct (solid lines) and indirect pathways (dotted lines). Specifically:

• Excitatory inputs from the cortical areas increase the inhibitory signal to GPe, causing a decrease in inhibitory activity to STN. Therefore, GPi will be more excited and then send more inhibition to the thalamus. In turn, cortical areas receive less excitation. This is the indirect pathway.
• D1 and D2, two dopaminergic receptors in the striatum are able to maintain balance so that the level of excitation is not out of order. In Parkinson's Disease patients, these receptors are disrupted by the damage to the substantia nigra pars compacta. As a result, there will be no inhibitory control for both GPi and GPe. An overproduction of inhibition causes thalamus to produce less excitatory signals back to the cortex. Muscles and posture become more rigid. 
• These excitatory input signals from the cortex are able to inhibit GPi through the direct pathway. As a result, it brings less inhibition to the thalamus, bringing more excitation to the cortex. Thus, projections back to the cortex have to go through the thalamus. Outputs from the GPi also go to the brain stem. 
• More recently, scientists have shown direct projection from the frontal cortex to STN that bypasses the striatum called the hyperdirect pathway. Thus, this pathway is also independent of D1/D2 influence. The exact function is still debatable.

Fig-2: The cortico-striatal loop showing indirect (dotted lines), direct pathway (solid lines), and hyper direct pathway. 

The BG receive most of their inputs from the cerebral cortex, notably the primary motor cortex, M1. And as mentioned, they also receive dopaminergic inputs from the SNpc. This has a strong implication; it means that the cortical information coming from the cerebral cortex can be modulated by the dopaminergic system. The way BG influence movement can be seen by studying two main motor pathways, i.e. direct and indirect pathways. Both pathways carry projections out through the GPi (globus pallidus interna) as the exit channels. Neurons from these output channels project back to the cerebral cortex and the brainstem through the ventromedial thalamus. The increased activity in one pathway will reduce movement execution, while the other, increase it. Probably, insights on the role of BG to movements come primarily from the studies with Parkinson's Disease patients.

Fig-3: The anatomical divisions of Basal Ganglia and Cerebellum, taken from [1, 2].

What is Cerebellum?
The cerebellum is located posterior to the brainstem. It is smaller than the 'big brain', but contains almost double the number of neurons in it. The cerebellum exerts influence on the ipsilateral side of the body but contralateral to the motor cortex. Cross-sectionally, the cerebellum can be divided into:
(1) Outer gray matter: contains a repeated pattern of circuitry; see below.
(2) The inner white matter with 4 pairs of output nuclei.
(3) Cerebellar peduncles: like highways connecting the cerebellum and the rest of the brain.

White matter nuclei of the cerebellum are the fastigial, the anterior and posterior interposed, and the dentate nuclei. The inputs to the cerebellum are conveyed primarily through the inferior and middle cerebellar peduncles, whereas the outputs are conveyed primarily through the superior cerebellar peduncle. Like the cerebral cortex with its four lobes, we traditionally divide the cerebellum into four divisions: the vermis, intermediate zone, lateral hemisphere, and the flocculonodular zone; the areas best seen if we unroll the cerebellum.

The cerebellum is intimately connected with the motor nuclei in the brainstem, cortical areas, and the thalamus. Frontal motor and parietal lobules are the principal cortical inputs to the cerebellum (Glickstein, 1980s). Refer to my diagram below. Based on the functional circuitry, there are 3 different divisions of the cerebellum:

1. The vestibulocerebellum regulates balance during stance and gait and controls eye movements. It has afferent connections to the vestibular system.
2. The spinocerebellum regulates movement execution of the body and limbs. This is achieved based on somatosensory afferents from distal and proximal limbs, trunk, and other body parts from the spinal ascending tracts. It also receives sensory information from the audio-visual and face areas. Adrian & Snider (c. 1940) found that there is a somatotopic map represented in the area of the vermis and paravermis. Outputs from interposed nuclei are connected to the lateral descending tracts, whereas fastigial nuclei to the more ventromedial tracts. Spinocerebellar circuits modulate movements by monitoring incoming sensory inputs and perform the online adjustment. 
3. The cerebrocerebellum is involved in skilled, timely, and accurate movement planning. It is thought that this area involves cognitive functions. Consistent with this notion, it is the most extensive area in humans, more than that in monkeys. It has direct connections with the motor cortex through pontine nuclei that loop back to the cerebral cortex through the thalamus. 

Fig-4: Summary of 3 functional pathways of the cerebellum shown with their INPUT and OUTPUT connections. 

Cerebellar synaptic organization
The cerebellar gray matter layer contains an intricate, repeated pattern of 'computational' circuitry that is shown in Fig-5. There are two main axons of cerebellar inputs: mossy fibers and climbing fibers. These two types of fibers provide a strong excitatory influence on the cerebellum.

1. Mossy fibers carry information through two pathways. First, direct projections from the spinal cord such as somatic information from skin and muscles. The projections are collectively known as spinocerebellar tracts. Second, indirect projections by going through different brainstem nuclei, e.g. pontine nucleus and reticular formations. Mossy fibers influence Purkinje cells indirectly through inhibitory cerebellar interneurons.
2. Climbing fibers carry information strictly from the inferior olive nucleus located at the midbrain. This structure, in turn, receives axons from the vestibular nuclei, tectum, dorsal column nuclei, and cortex. Climbing fibers make direct contact with the Purkinje cells. Unlike mossy fibers, climbing fibers have the capability to elicit complex spikes. Scientists believe that these spikes occur mostly when there is sensory prediction error e.g. during learning or adaptation.

Purkinje cells are the only output from the cerebellar cortex to deep white matter. They have massive dendritic branching, allowing multiple synaptic inputs, and carry post-synaptic inhibitory (GABAergic) outputs to the cerebellar nuclei.

Deep cerebellar nuclei always yield excitatory outputs to the thalamus before sending the flow back to the cerebral cortex. However, this excitatory state is modulated by two things: direct influence from mossy/climbing fibers and from the Purkinje cells.



Fig-5 Synaptic organization within the cerebellum. There are multiple loops within the circuitry. The dentate nucleus is the largest cerebellar nuclei that influence the motor cortex via the thalamus. Thus, the cerebellum is able to influence voluntary movement.



References
[1]  Chapter 42 - Cerebellum. In Kandel E.R. et. al. (2000). Principles of Neural Science 4e, McGraw-Hill.
[2]  Chapter 43 - Basal Ganglia. In Kandel E.R. et. al. (2000). Principles of Neural Science 4e, McGraw-Hill.
[3]  Chapter 8 - Control of Movement. In Carlson, Neil R. (2013). Physiology of Behavior 11e. Pearson Education.